Neurodegenerative diseases afflict more than 30 million of individuals worldwide. Current therapies target the symptoms of these diseases, generally with only modest efficacy.
Alzheimer's disease (AD), the most prevalent neurodegenerative disease, is characterized clinically by progressive memory loss and cognitive dysfunction, and pathologically by the development in the brain of intracellular neurofibrillary tangles containing abnormally hyperphosphorylated tau and extracellular senile amyloid plaques constituted predominantly of β-amyloid (Aβ).
Recently, microglia, the resident immune cells of brain, have been considered to play an important role in the pathogenesis of neurodegenerative diseases, more specifically, microglia-mediated neuro-inflammation where microglia are activated has been implicated in the development of these diseases especially in AD and Parkinson's disease (PD). However, microglial activation is associated with production of an assortment of effector molecules that may have complex and mixed effects on Aβ clearance and neuronal survival. Also, based on recent studies, complete inhibition of microglial activation using non-steroidal anti-inflammatory drugs appears to show limited therapeutic benefits for the diseases. See e.g., Shie et al., Current Medicinal Chemistry, 2007 (14): 2865-2871; Hayden, et. al., Neurology, 2007 (69):275-282; Britschgi et al., Nat. Med., 2007 (13):408-4099; Shie et al., Brain Pathol., 2005 (15):134-138; Jin et al., Journal of Neuroinflammation, 2007 (4):2-11; and Gao et al., FASEB J., 2003 (17): 1957-1959.
Fine-tuning microglial activation may confer better means for the therapy. There is growing consensus that a favorable combination of reduced microglia-mediated neuro-inflammation and enhanced phagocytic activity of microglia is essential in slowing the progression of the neurodegenerative diseases.